1. Field of the Invention
The present invention relates to a piperidine derivative or a salt thereof, which has excellent antihistamine activity and antileukotriene activity, and is useful as a drug for the prevention and treatment of various allergic diseases.
2. Description of the Background
Histamine produces various complex biological actions via interaction with specific receptors in the membranes of cell surfaces. Action of histamine on H.sub.1 -receptors stimulates many smooth muscles to contract such as those in the bronchi. Contraction of the bronchi leads to restriction of the air passage into and out of the lungs as in asthma. Histamine also increases the permeability of the capillary walls so that more of the constituents of the plasma can escape into the tissue spaces, leading to an increase in the flow of lymph and its protein content, and formation of edema. Histamine H.sub.1 -receptor antagonists have been proven to be successful for the treatment of many allergic diseases, e.g., allergic rhinitis, dermatosis, urticaria, etc. However for the treatment of some severe allergic diseases such as asthma, histamine H.sub.1 -receptor antagonists have been found to be less effective.
Leukotrienes are a group of arachidonic acid metabolites which are collectively long-known `slow-reacting substance of anaphylaxis` (SRS-A). The biological action of leukotrienes include bronchoconstriction, mucus hypersecretion and pulmonary edema which all contribute to airway obstruction characteristic of asthma. Leukotrienes also possess chemotactic properties that attract leukocyte to sites of cellular injury and thus contribute to inflammation. In contrast to histamine, leukotrienes induce prolonged bronchoconstriction. Clinical trials of the compounds known to have capability to block leuokotriene D.sub.4 (LTD.sub.4) action on its receptors have shown that these compounds are effective for the treatment of asthma (Manning, P. J. et al: N. Engl. J. Med. 1990, 323, 1736-1739 and Taylor, I. K. et al: Lancer 1991, 337, 690-694).
Accordingly, compounds with antagonistic activity on both histamine H.sub.1 -receptors and leukotriene LTD.sub.4 -receptors are potentially useful therapeutics for the prevention and treatment of allergic diseases in general and asthma in particular.
Many piperidine derivatives have been reported to exhibit both antihistamine activity and antileukotriene activity (Foxwell, M. H. et al: J. Allergy Clin. Immunol. 1988, 81, 250; European patent publication No. 0399414A1; Japanese patent publication (kokai) No. 271458/1991; and Japanese patent publication (kokai) No. 182467/1992).
These conventional piperidine derivatives, however, exhibit only insufficient pharmacological activities. Accordingly, compounds having potent antihistamine and antileukotriene activities with extensively reduced adverse side-effects such as a central nervous system inhibitory action have still been desired.
Under the above circumstances, the present inventors have carried out earnest studies for providing a compound which possesses excellent antihistamine activity and antileukotriene activity, is very safe and is useful for the prevention and treatment of asthma, allergic rhinitis, allergic dermatosis, urticaria, etc.